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1.
Cell Biol Int ; 44(10): 2140-2152, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32678496

RESUMO

The pyroptosis is a causative agent of rheumatoid arthritis, a systemic autoimmune disease merged with degenerative articular cartilage. Nevertheless, the precise mechanism of extracellular acidosis on chondrocyte pyroptosis is largely unclear. Acid-sensing ion channels (ASICs) belong to an extracellular H+ -activated cation channel family. Accumulating evidence has highlighted activation of ASICs induced by extracellular acidosis upregulate calpain and calcineurin expression in arthritis. In the present study, to investigate the expression and the role of acid-sensing ion channel 1a (ASIC1a), calpain, calcineurin, and NLRP3 inflammasome proteins in regulating acid-induced articular chondrocyte pyroptosis, primary rat articular chondrocytes were subjected to different pH, different time, and different treatments with or without ASIC1a, calpain-2, and calcineurin, respectively. Initially, the research results showed that extracellular acidosis-induced the protein expression of ASIC1a in a pH- and time-dependent manner, and the messenger RNA and protein expressions of calpain, calcineurin, NLRP3, apoptosis-associated speck-like protein, and caspase-1 were significantly increased in a time-dependent manner. Furthermore, the inhibition of ASIC1a, calpain-2, or calcineurin, respectively, could decrease the cell death accompanied with the decreased interleukin-1ß level, and the decreased expression of ASIC1a, calpain-2, calcineurin, and NLRP3 inflammasome proteins. Taken together, these results indicated the activation of ASIC1a induced by extracellular acidosis could trigger pyroptosis of rat articular chondrocytes, the mechanism of which might partly be involved with the activation of calpain-2/calcineurin pathway.


Assuntos
Canais Iônicos Sensíveis a Ácido/fisiologia , Artrite Experimental , Calcineurina/metabolismo , Calpaína/metabolismo , Condrócitos , Piroptose , Animais , Artrite Experimental/mortalidade , Artrite Experimental/patologia , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Sprague-Dawley
3.
Bioorg Med Chem ; 26(12): 3158-3165, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29699911

RESUMO

A series of new 6-styryl-naphthalene-2-amidrazone derivatives were synthesized and evaluated as potential ASIC1a inhibitors. Among them, compound 5e showed the most activity to inhibit [Ca2+]i. elevation in acid-induced articular chondrocytes. Together with the important role of ASIC1a in the pathogenesis of tissue acidification diseases including rheumatoid arthritis, these results might provide a meaningful hint or inspiration in developing drugs targeting at tissue acidification diseases.


Assuntos
Ácidos Carboxílicos/química , Desenho de Fármacos , Agonistas de Canais de Sódio/síntese química , Canais Iônicos Sensíveis a Ácido/química , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Cálcio/metabolismo , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Condrócitos/citologia , Condrócitos/metabolismo , Naftalenos/química , Ratos , Agonistas de Canais de Sódio/química , Agonistas de Canais de Sódio/farmacologia , Relação Estrutura-Atividade
4.
Biochim Biophys Acta Mol Basis Dis ; 1864(1): 162-177, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28986307

RESUMO

The acute-phase proinflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) demonstrate high-level expression and pleiotropic biological effects, and contribute to the progression and persistence of rheumatoid arthritis (RA). Acid hydrarthrosis is also an important pathological characteristic of RA, and the acid-sensing ion channel 1a (ASIC1a) plays a critical role in acidosis-induced chondrocyte cytotoxicity. However, the roles of IL-1ß and TNF-α in acid-induced apoptosis of chondrocytes remain unclear. Rat adjuvant arthritis and primary articular chondrocytes were used as in vivo and in vitro model systems, respectively. ASIC1a expression in articular cartilage was increased and highly colocalized with nuclear factor (NF)-κB expression in vivo. IL-1ß and TNF-α could upregulate ASIC1a expression. These cytokines activated mitogen-activated protein kinase and NF-κB pathways in chondrocytes, while the respective inhibitors of these signaling pathways could partially reverse the ASIC1a upregulation induced by IL-1ß and TNF-α. Dual luciferase and gel-shift assays and chromatin immunoprecipitation-polymerase chain reaction demonstrated that IL-1ß and TNF-α enhanced ASIC1a promoter activity in chondrocytes by increasing NF-κB DNA-binding activities, which was in turn prevented by the NF-κB inhibitor ammonium pyrrolidinedithiocarbamate. IL-1ß and TNF-α also decreased cell viability but enhanced LDH release, intracellular Ca2+ concentration elevation, loss of mitochondrial membrane potential, cleaved PARP and cleaved caspase-3/9 expression, and apoptosis in acid-stimulated chondrocytes, which effects could be abrogated by the specific ASIC1a inhibitor psalmotoxin-1 (PcTX-1), ASIC1a-short hairpin RNA or calcium chelating agent BAPTA-AM. These results indicate that IL-1ß and TNF-α can augment acidosis-induced cytotoxicity through NF-κB-dependent up-regulation of ASIC1a channel expression in primary articular chondrocytes.


Assuntos
Acidose/patologia , Apoptose/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Interleucina-1beta/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Canais Iônicos Sensíveis a Ácido/genética , Canais Iônicos Sensíveis a Ácido/metabolismo , Acidose/genética , Acidose/metabolismo , Animais , Apoptose/genética , Artrite Experimental/genética , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Cartilagem Articular/fisiologia , Células Cultivadas , Condrócitos/fisiologia , Masculino , NF-kappa B/metabolismo , NF-kappa B/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
5.
Gene ; 642: 230-240, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29141196

RESUMO

Acid hydrarthrosis is another important pathological character in rheumatoid arthritis (RA), and acid-sensing ion channel 1a (ASIC1a) plays a destructive role in acidosis-induced articular chondrocyte cytotoxicity. Recently, ASIC2a has been reported to possess neuroprotective effect on acidosis-induced injury of neuronal cells. However, whether ASIC2a has an enhanced effect on the protective effect of blocking ASIC1a and ASIC3 against acid-induced chondrocyte apoptosis is still unclear. The aim of present study was to investigate the chondroprotective effect of ASIC2a with PcTx1 (ASIC1a specific blocker) and APETx2 (ASIC3 specific blocker) on acidosis-induced chondrocyte apoptosis. Our results revealed that acid (pH 6.0) decreased the cell viability and induced apoptosis of articular chondrocytes. PcTx1 and APETx2 combination significantly attenuated acidosis-induced chondrocyte cytotoxicity due to inhibit apoptosis, and this role could be enhanced by ASIC2a overexpression compared with the PcTx1 and APETx2 combination alone group. Moreover, both the [Ca2+]i levels and the levels of phosphorylated ERK1/2 as well as p38 were further reduced in acidosis-induced chondrocytes after ASIC2a overexpression in the presence of PcTx1 and APETx2. Furthermore, ASIC2a overexpression also reduced acid-induced the expression of ASIC1a. In addition, ASIC2a overexpression further promoted the PcTx1 and APETx2-increased levels of type II collagen in acidosis-induced chondrocytes. Taken together, the current data suggested that ASIC2a overexpression might enhance the anti-apoptotic and protective role of PcTx1 and APETx2 against acid-induced rat articular chondrocyte apoptosis by regulating ASIC1a expression and the [Ca2+]i levels and at least in part, suppressing p38 and ERK1/2 MAPK signaling pathways.


Assuntos
Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Canais Iônicos Sensíveis a Ácido/genética , Acidose/genética , Ácidos Alcanossulfônicos/efeitos adversos , Condrócitos/efeitos dos fármacos , Morfolinas/efeitos adversos , Canais Iônicos Sensíveis a Ácido/metabolismo , Acidose/induzido quimicamente , Acidose/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Condrócitos/citologia , Condrócitos/metabolismo , Venenos de Cnidários/farmacologia , Colágeno Tipo II/metabolismo , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Vetores Genéticos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Peptídeos/farmacologia , Plasmídeos/genética , Ratos , Venenos de Aranha/farmacologia
6.
Bioorg Med Chem Lett ; 27(8): 1803-1807, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28284806

RESUMO

A series of new (2E,4E)-1-(substitutedphenyl)-5-(substitutedphenyl)penta-2,4-dien-1-one derivatives were designed and synthesized. Compounds 3i, 3k were determined by X-ray. All of the compounds have been screened for their anti-inflammatory activity characterized by evaluating their inhibition against LPS-induced IL-6 and TNF-α release in cell RAW 264.7 stimulated with LPS. Compound 3i showed the highest anti-inflammatory activity on decreasing IL-6 and TNF-α. The further study showed that title compound 3i inhibited expression of proteins p-p65, iNOS, COX-2 LPS-induced. Immunofluorescence also revealed compound 3i could lightly reduce activation p65 in nuclei. These results indicate that compound 3i anti-inflammatory role may partly due to its inhibitory effect on the NF-κB signaling pathway.


Assuntos
Alcadienos/química , Alcadienos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Animais , Interleucina-6/imunologia , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Camundongos , Modelos Moleculares , Células RAW 264.7 , Fator de Necrose Tumoral alfa/imunologia
7.
Aging Dis ; 7(4): 491-501, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27493834

RESUMO

Degenerative diseases often strike older adults and are characterized by progressive deterioration of cells, eventually leading to tissue and organ degeneration for which limited effective treatment options are currently available. Acid-sensing ion channels (ASICs), a family of extracellular H(+)-activated ligand-gated ion channels, play critical roles in physiological and pathological conditions. Aberrant activation of ASICs is reported to regulate cell apoptosis, differentiation and autophagy. Accumulating evidence has highlighted a dramatic increase and activation of ASICs in degenerative disorders, including multiple sclerosis, Parkinson's disease, Huntington's disease, intervertebral disc degeneration and arthritis. In this review, we have comprehensively discussed the critical roles of ASICs and their potential utility as therapeutic targets in degenerative diseases.

8.
Curr Top Med Chem ; 16(30): 3582-3589, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27086791

RESUMO

Oxazole derivatives are found to have a variety of biological activities. A large number of studies have revealed their outstanding anticancer activities. Here we review four different types of oxazole derivatives with anticancer potential reported over the last ten years. We focus our discussion on their activity, selectivity in different cancer cell lines, mechanisms of action, and their structural evolution.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Oxazóis/química , Antineoplásicos/química
9.
J Huazhong Univ Sci Technolog Med Sci ; 33(3): 375-378, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23771663

RESUMO

This study aimed to investigate the therapeutical effects of Rhodiola rosea extract on rats with type 2 diabetic nephropathy (DN). The rat type 2 DN model was established by high fat and high calorie feeding and intravenous injection of streptozocin (STZ). Wistar rats were randomly divided into normal group, control group, low dose Rhodiola rosea group, high dose Rhodiola rosea group and Captopril group. Oral glucose tolerance test (OGTT) was performed to determine the impairment of glucose tolerance in the established animal model. A series of parameters including fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), creatinine clearance rate (Ccr), 24-h urinary albumin (UA), the ratio of kidney mass/body weight (renal index) and glomerular area were examined after 8 weeks. Moreover, the expression of transforming growth factor (TGF)-ß1 in renal tissues was detected by using immunohistochemisty. At the end of the eighth week, FBG, TC, TG, Ccr, 24-h urinary albumin, the ratio of kidney mass/body weight and glomerular area were significantly reduced in Rhodiola rosea extract treatment groups as compared with those in control group. TGF-ß1 expression in renal tissues of Rhodiola rosea extract treatment groups was also significantly decreased as compared with that of control group. These results indicate that Rhodiola rosea extract may have a protective effect on early nephropathy in diabetic rats, which might be related to the decrease of the renal expression of TGF-ß1.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Extratos Vegetais/administração & dosagem , Rhodiola/química , Animais , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/patologia , Medicamentos de Ervas Chinesas/administração & dosagem , Etanol/química , Taxa de Filtração Glomerular/efeitos dos fármacos , Masculino , Extratos Vegetais/química , Ratos , Ratos Wistar , Resultado do Tratamento
10.
Zhong Yao Cai ; 35(5): 699-702, 2012 May.
Artigo em Chinês | MEDLINE | ID: mdl-23213729

RESUMO

OBJECTIVE: To establish a simple, rapid and usable new method of processing on Rhei Radix Et Rhizoma and the quality control standard on its processing products. METHODS: The studies of processing on Rhei Radix Et Rhizoma were proceed using yellow rice wine as solvent, through spray, soften and dry at 60-70 degrees C. The contents of total and uncombined chrysophanol and emodin in multi-Rhei Radix Et Rhizoma and its processing products were determined by HPLC. RESULTS: The new method of processing on Rhei Radix Et Rhizoma was simple, rapid and usable. The contents of uncombined chrysophanol and emodin in its processing products was 80%. CONCLUSION: This study provides a new method of processing on Rhei Radix Et Rhizoma and quality control standard on its processing products.


Assuntos
Antraquinonas/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Emodina/análise , Rheum , Tecnologia Farmacêutica/métodos , Cromatografia Líquida de Alta Pressão , Etanol/química , Controle de Qualidade , Rheum/química , Rizoma/química , Solventes/química , Temperatura , Vinho
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